POMC neurons of the hypothalamus are critical components of the neural circuitry controlling appetite, feeding, and metabolism. In addition they modulate the activity of other hypothalamic neurons which control reproduction, thyroid hormone levels, growth hormone secretion, prolactin secretion, and neuroendocrine stress responses. These neurons also are involved in the nervous system's endogenous analgesic and reward circuits. POMC is a prohormone that is postranslationally processed into several different biologically active neuropeptides. The most important of these neuropeptides within the hypothalamus are alpha-MSH, gamma-MSH, and the opioid beta-endorphin. The two MSH peptides are potent anorexigenic substances that play a fundamental role in modulating weight homeostasis. β-endorphin also modulates food intake by at least two distinct mechanisms. It can directly increase food intake when administered acutely, but it also modulates the neural circuitry underlying the rewarding aspects of food ingestion and thereby influences an organism's motivation to work to obtain food.
Genetic evidence in humans implicates the POMC gene in the regulation of weight and fat mass. Rare mutations causing null alleles result in a syndrome of adrenal cortical insufficiency, red hair, and obesity. The three components of the syndrome are secondary to losses of peripheral ACTH, peripheral MSH, and central MSH, respectively. However, a number of other gene association and quantitative trait loci analyses in human populations suggest a much more common role for the POMC gene in weight homeostasis.
The POMC promoter has been identified. For example, in the rat, 5′ flanking sequences form −323 to −34 are sufficient for correct spatial, temporal and hormonally regulated expression of POMC in the pituitary gland (e.g. see Liu et al., Mol. Cell. Biol. 12:3978–3990, 1992; Liu et al., Biochem. J. 312:827–832, 1995). In addition, a transgene including approximately 13 kilobases (kb) of the mouse POMC gene has been demonstrated to produce cell specific and developmentally regulated expression of POMC in transgenic mice (Young et al., J. Neurosci. 18:6631–6640, 1998). However, other specific nucleic acid elements involved in tissue specific expression, such as a POMC enhancer, have not been identified.